Pyridine imidazoles and aza-indoles as progesterone receptor modulators

ABSTRACT

The present invention is directed to novel heteroatom containing tetracyclic derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders mediated by one or more estrogen receptors. The compounds of the invention are useful in the treatment of disorders associated with the depletion of estrogen such as hot flashes, vaginal dryness, osteopenia and osteoporosis; hormone sensitive cancers and hyperplasia of the breast, endometrium, cervix and prostate; endometriosis, uterine fibroids, osteoarthritis and as contraceptive agents, alone or in combination with a progestogen or progestogen antagonist.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.60/622,580, filed Oct. 27, 2004, which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention is directed to novel pyridine imidazoles andaza-indole derivatives, the pharmaceutical compositions containing themand their use in the treatment or prevention of disorders and diseasesmediated by agonists and antagonists of the progesterone receptor. Theclinical usage of these compounds are related to hormonal contraception,the treatment and/or prevention of secondary dysmenorrhea, amenorrhea,dysfunctional uterine bleeding, uterine leiomyomata, endometriosis;polycystic ovary syndrome, carcinomas and adenocarcinomas of theendometrium, ovary, breast, colon, prostate, or minication of sideeffects of cyclic menstrual bleeding. Additional uses of the inventioninclude stimulation of food intake.

BACKGROUND OF THE INVENTION

Intracellular receptors are a class of structurally related proteinsinvolved in the regulation of gene proteins. Steroid receptors are asubset of these receptors, including the progesterone receptors (PR),androgen receptors (AR), estrogen receptors (ER), glucocorticoidreceptors (GR) and mineralocorticoid receptors (MR). Regulation of agene by such factors requires the intracellular receptor and acorresponding ligand which has the ability to selectively bind to thereceptor in a way that affects gene transcription.

Progesterone receptor modulators (progestagens) are known to play animportant role in mammalian development and homeostasis. Progesterone isknown to be required for mammary gland development, ovulation and themaintenance of pregnancy. Currently, steroidal progestin agonists andantagonists are clinically approved for contraception, hormonereplacement therapy (HRT) and therapeutic abortion. Moreover, there isgood preclinical and clinical evidence for the value of progestinantagonists in treating endometriosis, uterine leiomyomata (fibroids),dysfunctional uterine bleeding and breast cancer.

The current steroidal progestagens have been proven to be quite safe andare well tolerated. Sometimes, however, side effects (e.g. breasttenderness, headaches, depression and weight gain) have been reportedthat are attributed to these steroidal progestagens, either alone or incombination with estrogenic compounds.

Steroidal ligands for one receptor often show cross-reactivity withother steroidal receptors. As an example, many progestagens also bind toglucocorticoid receptor. Non-steroidal progestagens have no molecularsimilarity with steroids and therefore one might also expect differencesin physicochemical properities, pharmacokinetic (PK) parameters, tissuedistribution (e.g. CNS versus peripheral) and, more importantly,non-steroidal progestagens may show no/less cross-reactivity to othersteroid receptors. Therefore, non-steroidal progestagens will likelyemerge as major players in reproductive pharmacology in the foreseeablefuture.

It was known that progesterone receptor existed as two isoforms,full-length progesterone receptor isoform (PR-B) and its shortercounterpart (PR-A). Recently, extensive studies have been implemented onthe progesterone receptor knockout mouse (PRKO, lacking both the A- andB-forms of the receptors), the mouse knockoutting specifically for thePR-A isoform (PRAKO) and the PR-B isoform (PRBKO). Different phenotypeswere discovered for PRKO, PRAKO and PRBKO in physiology studies in termsof fertility, ovulation uterine receptivity, uterine proliferation,proliferation of mammary gland, sexual receptivity in female mice,sexual activity in male mice and infanticide tendencies in male mice.These findings provided great challenge for synthetic chemists toconstruct not only selective progesterone receptor modulator (SPRM), butalso PR-A or PR-B selective progesterone receptor modulator.

SUMMARY OF THE INVENTION

The present invention provides novel pyridine imidazoles and aza-indolederivatives of the formula (I) or (II):

wherein

R₁ and R₂ are independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl, aralkyl or heteroaryl-alkyl; wherein thecycloalkyl, aralkyl or heteroaryl-alkyl group is optionally substitutedwith one or more substituents independently selected from halogen,hydroxy, alkyl, alkoxy, —SH, —S(alkyl), SO₂(alkyl), NO₂, CN, CO₂H,—OR^(C), —SO₂—NR^(D)R^(E), —NR^(D)R^(E), NR^(D)—SO₂—R^(F),-(alkyl)₀₋₄-C(O)NR^(D)R^(E), (alkyl)₀₋₄-NR^(D)—C(O)—R^(F),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-NR^(D)R^(E);

wherein R^(C) is selected from the group consisting of alkyl,cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl,heteroaryl-alkyl, heterocycloalkyl and heterocycloalkyl-alkyl; whereinthe cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl,heteroaryl-alkyl, heterocycloalkyl or heterocycloalkyl-alkyl group isoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, alkoxy, —SH, —S(alkyl),SO₂(alkyl), NO₂, CN, CO₂H, R^(C), —SO₂—NR^(D)R^(E), NR^(D)R^(E),NR^(D)—SO₂—R^(F), -(alkyl)₀₋₄-C(O)—NR^(D)R^(E),-(alkyl)₀₋₄-NR^(D)—C(O)—R^(F),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-NR^(D)R^(E),

wherein Q is selected from the group consisting of O, S, NH, N(alkyl)and —CH═CH—;

wherein R^(D) and R^(E) are each independently selected from the groupconsisting of hydrogen and alkyl; alternatively R^(D) and R^(E) aretaken together with the nitrogen atom to which they are bound to form a4 to 8 membered ring selected from the group consisting of heteroaryl orheterocycloalkyl; wherein the heteroaryl or heterocycloalkyl group isoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino,alkylamino, dialkylamino, nitro or cyano;

wherein R^(F) is selected from the group consisting of hydrogen, alkyl,cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl,heteroaryl-alkyl, heterocycloalkyl and heterocycloalkyl-alkyl; whereinthe cycloalkyl, aryl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl orheterocycloalkyl-alkyl group is optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, alkyl,alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;

R₃ is selected from the group consisting of halogen, CF₃, hydroxy,R^(C), nitro, cyano, SO₂(alkyl), —C(O)R^(G), —C(O)OR^(G), —OC(O)R^(G),—OC(O)OR^(G), —OC(O)N(R^(G))₂, —N(R^(G))C(O)R^(G), —OSi(R^(G))₃—OR^(G),—SO₂N(R^(G))₂, —O-(alkyl)₁₋₄-C(O)R^(G), —O-(alkyl)₁₋₄-C(O)OR^(G), aryland heteroaryl, wherein aryl or heteroaryl is optionally substitutedwith one or more substituents independently selected from alkyl,halogenated alkyl, alkoxy, halogen, hydroxy, nitro, cyano, —OC(O)-alkylor —C(O)O-alkyl;

wherein each R^(G) is independently selected from hydrogen, alkyl, aryl,aralkyl; wherein the alkyl, aryl or aralkyl group is optionallysubstituted with one or more substituents independently selected fromalkyl, halogenated alkyl, alkoxy, halogen, hydroxy, nitro, cyano,—OC(O)-alkyl or —C(O)O-alkyl;

alternatively two R^(G) groups are taken together with the nitrogen atomto which they are bound to form a heterocycloalkyl group; wherein theheterocycloalkyl group is optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, alkyl,alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;

R₄ is selected from the group consisting of hydrogen, acetyl,SO₂(alkyl), alkyl, cycloalkyl, aralkyl or heteroaryl-alkyl; wherein thecycloalkyl, aralkyl or heteroaryl-alkyl group is optionally substitutedwith one or more substituents independently selected from halogen,hydroxy, alkyl, alkoxy, —SH, —S(alkyl), SO₂(alkyl), NO₂, CN, CO₂H,—OR^(C), —SO₂—NR^(D)R^(E), NR^(D)R^(E), NR^(D)—SO₂—R^(F),-(alkyl)₀₋₄-C(O)NR^(D)R^(E), (alkyl)₀₋₄-NR^(D)—C(O)—R^(F),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-NR^(D)R^(E),

wherein R^(C) is selected from the group consisting of alkyl,cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl,heteroaryl-alkyl, heterocycloalkyl and heterocycloalkyl-alkyl; whereinthe cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl,heteroaryl-alkyl, heterocycloalkyl or heterocycloalkyl-alkyl group isoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, alkoxy, —SH, —S(alkyl),SO₂(alkyl), NO₂, CN, CO₂H, R^(C), —SO₂—NR^(D)R^(E), NR^(D)R^(E),NR^(D)—SO₂—R^(F), -(alkyl)₀₋₄—C(O)—NR^(D)R^(E),-(alkyl)₀₋₄-NR^(D)—C(O)—R^(F),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-NR^(D)R^(E),

wherein Q is selected from the group consisting of O, S, NH, N(alkyl)and —CH═CH—;

wherein R^(D) and R^(E) are each independently selected from the groupconsisting of hydrogen and alkyl; alternatively R^(D) and R^(E) aretaken together with the nitrogen atom to which they are bound to form a4 to 8 membered ring selected from the group consisting of heteroaryl orheterocycloalkyl; wherein the heteroaryl or heterocycloalkyl group isoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino,alkylamino, dialkylamino, nitro or cyano;

wherein R^(F) is selected from the group consisting of hydrogen, alkyl,cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl,heteroaryl-alkyl, heterocycloalkyl and heterocycloalkyl-alkyl; whereinthe cycloalkyl, aryl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl orheterocycloalkyl-alkyl group is optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, alkyl,alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;

or a pharmaceutically acceptable salt thereof.

The compounds of this invention may contain an asymmetric carbon atomand some of the compounds of this invention may contain one or moreasymmetric centers and may thus give rise to optical isomers anddiastereomers. While shown without respect to stereochemistry in Formula1 and 2, the present invention includes such optical isomers anddiastereomersl as well as the racemic and resolved, enantiomericallypure S and R stereoisomersa dn pharmaceutically acceptable saltsthereof.

Illustrative of the invention is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and any of the compounds describedabove. An illustration of the invention is a pharmaceutical compositionmade by mixing any of the compounds described above and apharmaceutically acceptable carrier. Illustrating the invention is aprocess for making a pharmaceutical composition comprising mixing any ofthe compounds described above and a pharmaceutically acceptable carrier.

Exemplifying the invention are methods of treating a disorder mediatedby one or more progesterone receptors in a subject in need thereofcomprising administering to the subject a therapeutically effectiveamount of any of the compounds or pharmaceutical compositions describedabove.

Illustrating the invention is a method of contraception comprisingadministering to a subject in need thereof co-therapy with atherapeutically effective amount of a compound of formula (I) with anestrogen or estrogen antagonist.

Another example of the invention is the use of any of the compoundsdescribed herein in the preparation of a medicament for treating: (a)dysfunctional bleeding, (b) endometriosis, (c) uterine leiomyomata, (d)secondary amenorrhea, (e) polycystic ovary syndrome, (f) carcinomas andadenocarcinomas of the endometrium, ovary, breast, colon, prostate, (g)minication of side effects of cyclid menstrual bleeding and for (h)contraception and i) stimulation of food intake in a subject in needthereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is further directed to a compound of formula (I)or (II):

wherein R₁, R₂, R₃ and R₄ are as herein defined, useful for thetreatment of disorders mediated by an progesterone receptor. Moreparticularly, the compounds of the present invention are useful for thetreatment and prevention of disorders mediated by the progesterone-A andprogesterone-B receptors. More preferably, the compounds of the presentinvention are tissue selective progesterone receptor modulators.

The compounds of the present invention are useful in the treatment ofdisorders associated with the depletion of progesterone, hormonesensitive cancers and hyperplasia, endometriosis, uterine fibroids,osteoarthritis and as contraceptive agents, alone or in combination witha estrogen or a partial estrogen antagonist.

The compounds of the present invention are useful in the treatment ofdisorders associated with the depletion of progesterone, secondaryamenorrhea, dysfunctional bleeding, uterine leiomyomata, endometriosis;polycystic ovary syndrome, carcinomas and adenocarcinomas of theendometrium, ovary, breast, colon, prostate, or minication of sideeffects of cyclid menstrual bleeding, and as contraceptive agents, aloneor in combination with a estrogen or restrogen antagonist.

In an embodiment of the present invention R₁, R₂ are both methyl groups.In another embodiment of the present invention R₁, R₂ are connected by—(CH₂)₄— to form a 5-membered spiro ring. In another embodiment of thepresent invention R₁, R₂ are connected by —(CH₂)₅— to form a 6-memberedspiro ring.

In an embodiment of the present invention R₃ is selected from halogen,CN, CF₃, NO₂ or SO₂(alkyl) group. In another embodiment of the presentinvention R₃ is selected from aryl, heteroaryl groups, wherein aryl orheteroaryl groups are mono-, di-, or tri-substituted by halogen, NO₂,CF₃, CN, O(alkyl).

In an embodiment of the present invention R₄ is selected from hydrogen,acetyl or SO₂(alkyl), lower alkyl, aralkyl, heteroarylalkyl.

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts. Thus, representative pharmaceutically acceptable salts includethe following:

acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium edetate, camsylate, carbonate, chloride,clavulanate, citrate, dihydrochloride, acetate, edisylate, estolate,esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,tosylate, triethiodide and valerate.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

As used herein, the term “progestogen antagonist” shall includemifepristone, J-867 (Jenapharm/TAP Pharmaceuticals), J-956(Jenapharm/TAP Pharmaceuticals), ORG-31710 (Organon), ORG-32638(Organon), ORG-31806 (Organon), onapristone and PRA248 (Wyeth).

As used herein, unless otherwise noted, “halogen” shall mean chlorine,bromine, fluorine and iodine.

As used herein, unless otherwise noted, the term “alkyl” whether usedalone or as part of a substituent group, include straight and branchedchain compositions of one to eight carbon atoms. For example, alkylradicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, t-butyl, pentyl and the like. Unless otherwise noted, “lower”when used with alkyl means a carbon chain composition of 1-4 carbonatoms. Similarly, the group “-(alkyl)₀₋₄-”, whether alone or as part ofa large substituent group, shall me the absence of an alkyl group or thepresence of an alkyl group comprising one to four carbon atoms. Suitableexamples include, but are not limited to —CH₂—, —CH₂CH₂—, CH₂—CH(CH₃)—,CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂—, CH₂CH₂CH₂CH₂—, and the like.

As used herein, unless otherwise noted, “alkoxy” shall denote an oxygenether radical of the above described straight or branched chain alkylgroups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy,n-hexyloxy and the like.

As used herein, unless otherwise noted, “aryl” shall refer tounsubstituted carbocyclic aromatic groups such as phenyl, naphthyl, andthe like.

As used herein, unless otherwise noted, “aralkyl” shall mean any loweralkyl group substituted with an aryl group such as phenyl, naphthyl andthe like. Suitable examples include benzyl, phenylethyl, phenylpropyl,naphthylmethyl, and the like.

As used herein, unless otherwise noted, the term “cycloalkyl” shall meanany stable 3-8 membered monocyclic, saturated ring system, for examplecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl.

As used herein, unless otherwise noted, the term “cycloalkyl-alkyl”shall mean any lower alkyl group substituted with a cycloalkyl group.Suitable examples include, but are not limited to cyclohexyl-methyl,cyclopentyl-methyl, cyclohexyl-ethyl, and the like.

As used herein, unless otherwise noted, the terms “acyloxy” shall mean aradical group of the formula —O—C(O)—R where R is alkyl, aryl oraralkyl, wherein the alkyl, aryl or aralkyl is optionally substituted.As used herein, the term “carboxylate” shall mean a radical group of theformula —C(O)O—R where R is alkyl, aryl or aralkyl, wherein the alkyl,aryl or aralkyl is optionally substituted.

As used herein, unless otherwise noted, “heteroaryl” shall denote anyfive or six membered monocyclic aromatic ring structure containing atleast one heteroatom selected from the group consisting of O, N and S,optionally containing one to three additional heteroatoms independentlyselected from the group consisting of O, N and S; or a nine or tenmembered bicyclic aromatic ring structure containing at least oneheteroatom selected from the group consisting of O, N and S, optionallycontaining one to four additional heteroatoms independently selectedfrom the group consisting of O, N and S. The heteroaryl group may beattached at any heteroatom or carbon atom of the ring such that theresult is a stable structure.

Examples of suitable heteroaryl groups include, but are not limited to,pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, purazolyl, isoxazolyl,isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl,isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl,benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl,isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pteridinyl, and the like.

As used herein, unless otherwise noted, the term “heteroaryl-alkyl”shall mean any lower alkyl group substituted with a heteroaryl group.Suitable examples include, but are not limited to pyridyl-methyl,isoquinolinyl-methyl, thiazolyl-ethyl, furyl-ethyl, and the like.

As used herein, the term “heterocycloalkyl” shall denote any five toseven membered monocyclic, saturated or partially unsaturated ringstructure containing at least one heteroatom selected from the groupconsisting of O, N and S, optionally containing one to three additionalheteroatoms independently selected from the group consisting of O, N andS; or a nine to ten membered saturated, partially unsaturated orpartially aromatic bicyclic ring system containing at least oneheteroatom selected from the group consisting of O, N and S, optionallycontaining one to four additional heteroatoms independently selectedfrom the group consisting of O, N and S. The heterocycloalkyl group maybe attached at any heteroatom or carbon atom of the ring such that theresult is a stable structure.

Examples of suitable heteroaryl groups include, but are not limited to,pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl, imidazolidinyl,pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl, morpholinyl,dithianyl, thiomorpholinyl, piperazinyl, trithianyl, indolinyl,chromenyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl, and thelike.

As used herein, unless otherwise noted, the term“heterocycloalkyl-alkyl” shall mean any lower alkyl group substitutedwith a heterocycloalkyl group. Suitable examples include, but are notlimited to piperidinyl-methyl, piperazinyl-methyl, piperazinyl-ethyl,morpholinyl-methyl, and the like.

When a particular group is “substituted” (e.g., cycloalkyl, aryl,heteroaryl, heterocycloalkyl), that group may have one or moresubstituents, preferably from one to five substituents, more preferablyfrom one to three substituents, most preferably from one to twosubstituents, independently selected from the list of substituents.Additionally when aralkyl, heteroaryl-alkyl, heterocycloalkyl-alkyl orcycloalkyl-alkyl group is substituted, the substituent(s) may be on anyportion of the group (i.e. the substituent(s) may be on the aryl,heteroaryl, heterocycloalkyl, cycloalkyl or the alkyl portion of thegroup.)

With reference to substituents, the term “independently” means that whenmore than one of such substituents is possible, such substituents may bethe same or different from each other.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenylC₁-C₆alkylaminocarbonylC₁-C₆alkyl”substituent refers to a group of the formula

Abbreviations used in the specification, particularly the Schemes andExamples, are as follows

Ac Acetyl group (—C(O)—CH₃) DCM Dichloromethane DMF Dimethyl formamideERT Estrogen replacement therapy Et ethyl (i.e. —CH₂CH₃) EtOAc Ethylacetate FBS Fetal bovine serum HPLC High pressure liquid chromatographyHRT Hormone replacement therapy MeOH Methanol Ph Phenyl TEA or Et₃NTriethylamine THF Tetrahydrofuran TsOH Toluene sulfonic acid

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated. Wherein the present inventiondirected to co-therapy comprising administration of one or morecompound(s) of formula I and a progestogen or progestogen antagonist,“therapeutically effective amount” shall mean that amount of thecombination of agents taken together so that the combined effect elicitsthe desired biological or medicinal response. For example, thetherapeutically effective amount of co-therapy comprising administrationof a compound of formula I and progestogen would be the amount of thecompound of formula I and the amount of the progestogen that when takentogether or sequentially have a combined effect that is therapeuticallyeffective. Further, it will be recognized by one skilled in the art thatin the case of co-therapy with a therapeutically effective amount, as inthe example above, the amount of the compound of formula I and/or theamount of the progestogen or progestogen antagonist individually may ormay not be therapeutically effective.

As used herein, the term “co-therapy” shall mean treatment of a subjectin need thereof by administering one or more compounds of formula I witha progestogen or progestogen antagonist, wherein the compound(s) offormula I and progestogen or progestogen antagonist are administered byany suitable means, simultaneously, sequentially, separately or in asingle pharmaceutical formulation. Where the compound(s) of formula Iand the progestogen or progestogen antagonist are administered inseparate dosage forms, the number of dosages administered per day foreach compound may be the same or different. The compound(s) of formula Iand the progestogen or progestogen antagonist may be administered viathe same or different routes of administration. Examples of suitablemethods of administration include, but are not limited to, oral,intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal,and rectal. Compounds may also be administered directly to the nervoussystem including, but not limited to, intracerebral, intraventricular,intracerebroventricular, intrathecal, intracisternal, intraspinal and/orperi-spinal routes of administration by delivery via intracranial orintravertebral needles and/or catheters with or without pump devices.The compound(s) of formula I and the progestogen or progestogenantagonist may be administered according to simultaneous or alternatingregimens, at the same or different times during the course of thetherapy, concurrently in divided or single forms.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

One skilled in the art will recognize that it may be necessary and/ordesirable to protect one or more of the R³ and/or R⁴ groups at any ofthe steps within the process described above. This may be accomplishedusing known protecting groups and know protection and de-protectionreagents and conditions, for example such as those described inProtective Groups in Organic Chemistry, ed. J. F. W. McOmie, PlenumPress, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups inOrganic Synthesis, John Wiley & Sons, 1991.

Compounds of formula (I) may be prepared according to the processoutlined in Scheme (I).

More particularly, a suitably substituted compound of formula (II),wherein X is halogen, CN, CF₃, NO₂, or SO₂(alkyl), a known compound orcompound prepared by known methods, is reacted with a compound offormula (III), a known compound, in an organic solvent such as acetone,THF, 1,4-dioxane, ethyl ether and the like, at a temperature in therange of about 0° C. to about 30° C., to yield the correspondingcompound of formula (IV). The cyclization of compound IV and alkyliodide (V) or alkyl diiodide (VI) can be affected under the organic basesuch as NaOMe, NaOEt, KOtBu, NaOtBu and the like or inorganic base, suchas NaOH, KOH, Na₂CO₃, NaHCO₃, K₂CO₃, Cs₂CO₃, KF and the like; in thepresence of organic solvent, such as MeOH, EtOH, iPrOH, tBuOH at atemperature in the range of about 0° C. to 100° C., to yield thecorresponding compound of formula (VII).

Preferably, compound of formula (VII), wherein X is Br or I, a compoundmade from Scheme I, can react further with aryl or heteroaryl boronicacid of formula R₃B(OH)₂, a known compound or a compound prepared fromknown methods, under the palladium (0) or palladium (+2) catalysts, suchas Pd(PPh₃)₄, Pd(OAc)₂ with PPh₃, PdCl₂(PPh₃)₂, or PdCl₂(dppf)₂ and thelike, in the presence of inorganic base, such as K₂CO₃, Na₂CO₃, KOAc,K₃PO₄, NaOAc, Cs₂CO₃, and the like, in the organic solvent such as1,4-dioxane, THF, toluene, with small amount of water; at a temperaturein the range of 0 to 125° C., to yield the corresponding compound offormula (VIII).

Preferably, compound of formula (X), a known compound prepared accordingto the procedure described in WO2003/082868, was deprotonated under anorganic base, such as nBuLi, LDA, NaHMDS and the like, in the aproticesolvent such as THF, ether, or hexane at a temperature in the range of−78° C. to −40° C.; the anion was then reacted with iodide of formulaR₁I or R₂I or diiodide of formula I—(R₁-R₂)—I to generate the compoundof formula (XI).

TABLE 1

ex. # R₁, R₂ R₃ MF 1-C3 Spirocyclohexane Br C₁₂H₁₃BrN₂O 3Spirocyclohexane 3-Cl-phenyl C₁₈H₁₇ClN₂O 1-C1 Dimethyl Br C₉H₉BrN₂O 2Dimethyl 3-Cl-phenyl C₁₅H₁₃ClN₂0 4 Dimethyl 3-CN-phenyl C₁₆H₁₃N3O 5Dimethyl Cl C9H9ClN2O 6 Spirocyclohexyl Cl C12H13ClN2O 7 Dimethyl3,5-di-F-phenyl C15H12F2N2O 8 Dimethyl 3-NO₂-phenyl C15H13N3O3 9Dimethyl 3-CF₃-phenyl C16H13F3N2O 10 Dimethyl 2,4-di-F-phenylC15H12F2N2O 11 Dimethyl 3,5-di-CF₃-phenyl C17H12F6N2O 12 Dimethyl3-MeO-phenyl C16H16N2O2 13 Dimethyl 3-F-phenyl C15H13FN2O 14 Dimethyl2-Cl-phenyl C15H13ClN2O 1-C2 spirocyclopentane Br C11H11BrN2O 15spirocyclohexane 3-F-phenyl C18H17FN2O 16 spirocyclohexane 3-MeO-phenylC19H20N2O2 17 spirocyclohexane 3,5-di-CF₃-phenyl C2OH16F6N2O 18spirocyclohexane 3-NO2-phenyl C18H17N3O3 19 spirocyclohexane3-CF₃-phenyl C19H17F3N2O 20 spirocyclohexane 3-CN-phenyl C19H17N3O 21spirocyclohexane 3,5-di-F-phenyl C18H16F2N2O 22 spirocyclohexane3,4-di-Cl-phenyl C18H16Cl2N2O 23 spirocyclohexane 2,4-di-F-phenylC18H16F2N2O 24 spirocyclopentane 3-Cl-phenyl C17H15ClN2O 25spirocyclopentane 3-CN-phenyl C18H15N3O 26 spirocyclopentane 3-F-phenylC17H15FN2O 27 spirocyclopentane 3-NO₂-phenyl C17H15N3O3 28spirocyclopentane 3,4-di-Cl-phenyl C17H14Cl2N2O 29 spirocyclopentane3,5-di-CF₃-phenyl C19H14F6N2O 30 spirocyclopentane 3-Cl-4-F-phenylC17H14ClFN2O

TABLE 2

Ex. # R₁, R₂ R₃ MF 31 Spirocyclohexane 3-F-phenyl C₂₃H₂₁FN₂O₃S 32Dimethyl 3-F-phenyl C₂₃H₂₁ClN₂O₃S

It is intended that the definition of any substituent or variable at aparticular location in a molecule be independent of its definitionselsewhere in that molecule. It is understood that substituents andsubstitution patterns on the compounds of this invention can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art as well as those methods set forth herein. It isfurther intended that when m is >1, the corresponding R⁴ substituentsmay be the same or different.

The compounds of the present invention can be used in the form of saltsderived from pharmaceutically or physiologically acceptable acids orbases. These salts include, but are not limited to, the following saltswith inorganic acids such as hydrochloric acid, sulfuric acid, nitricacid, phosphoric acid and as the case may be, such organic acids asacetic acid, oxalic acid, succinic acid, and maleic acid. Other saltsinclude salts with alkali metals or alkaline earth metals, such assodium, potassium, calcium or magnesium in the form of esters,carbamates and other conventional “pro-drug” forms, which, whenadministered in such form, convert to the active moiety in vivo.

This invention includes pharmaceutical compositions comprising one ormore compounds of this invention, preferably in combination with one ormore pharmaceutically acceptable carriers and/or excipients. Theinvention also includes methods of contraception and methods of treatingor preventing maladies associated with the progesterone receptor, themethods comprising administering to a mammal in need thereof apharmaceutically effective amount of one or more compounds as describedabove wherein R is alkyl, aryl, heteroary or alkylaryl groupI.

The progesterone receptor antagonists of this invention, used alone orin combination, can be utilized in methods of contraception and thetreatment and/or prevention of benign and malignant neoplastic disease.Specific uses of the compounds and pharmaceutical compositions ofinvention include the treatment and/or prevention of uterine myometrialfibroids, endometriosis, genign prostatic hypertrophy; carcinomas andadenocarcinomas of the endometrium, ovary, breast, colon, prostate,pituitary, meningioma and other hormone-depent tumors. Additional usesof the present progesterone receptor antagonists include thesynchronization of the estrus in livestock.

When used in contraception the progesterone receptor antagonists of thedurrent invention may be used either alone in a continuousadministration of between 0.1 and 500 mg per day, or alternatively usedin a different regimen which would entail 2-4 days of treatment with theprogesterone receptor antagonist after 21 days of a progestin. In thisregimen between 0.1 and 500 mg daily doses of the progestin (e.g.levonorgestrel, trimegestone, gestodene, norethistrone acetate,norgestimate or cyproterone acetate) would be followed by between 0.1and 500 mg daily doses of the progesterone receptor antagonists of thecurrent invention.

The progesterone receptor agonists of this invention, used alone or incombination, can also be utilized in methods of contraception and thetreatment and/or prevention of dysfunctional bleeding, uterineleiomyomata, endometriosis; polycystic ovary syncrome, carcinomas andadenocarcimomas of the endometrium, ovary, breast, colon, prostate.Additional uses of the invention include stimulation of food intake.

When used in contraception the progesterone receptor agonists of thedurrent invention are preferably used in combination or sequentiallywith an estrogen agonist (e.g. ethinyl estradiao). The preferred dose ofthe progesterone receptor agonist is 0.01 mg and 500 mg per day.

This invention also includes pharmaceutical compositions comprising oneor more compounds described herein, preferably in combination with oneor more pharmaceutically acceptable carriers or excipients. When thecompounds are employed for the above utilities, they may be combinedwith one or more pharmaceutically acceptable carriers, or excipients,for example, solvents, diluents and the like and may be administeredorally in such forms as tablets, caplules, dispersible powders,granules, or suspensions containing, for example, from about 0.05 to 5%of suspending agent, syrups containing, for example, from about 10 to50% of sugan, and elixirs containing, for example, from 20 to 50%ethanol, and the like, or parenterally in the form of sterile injectalesolutions or suspensions containing from about 0.05 to 5% suspendingagent in an isotonic medium. Such pharmaceutical preparations maycontain, for example, from about 25 to about 90% of the activeingredient in combination with the carrier, more usually between about5% and 60% by weight.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration and theseverity of the condition being treated. However, in general,satisfactory results are obtained when the compounds of the inventionare administered at a daily dosage of from about 0.5 to about 500 mg/kgof animal body weight, preferably given in dibided doses two to fourtimes a day, or in a sustained release from. For most large mammals, thetotal daily dosage is from about 1 to 100 mg, preferably from about 2 to80 mg Dosage froms suitable for internal use comprise from about 0.5 to500 mg of the active compound in intimate admixture with a solid orliquid pharmaceutically acceptable carrier. This dosage regimen may beadjusted to provide the optimal therapeutic respose. For example,several divided doses may be administered daily or the dose may beproportionally reduced as indicated by the exigencies of the therapeuticsituation.

These active compounds may be administered orally as well as byintervenous, imtramuscular, or subcutaneous routes. Solid carriersinclude starch, lactose, dicalcium phosphate, microcrystallinecellulose, sucrose and kaolin, while liquid carriers include sterilewater, polyethylene glycols, non-ionic surfactants and edible oils suchas corn, peanut and sesame oil, as are appropriate to the nature of theactive ingredient and the particular form of administration desired.Adjuvants customarily employed in the preparation of pharmaceuticalcompositions may be advantageously included, such as flavoring agents,coloring agents, preserving agents, and antioxidants, for example,vitamin E, ascorbic acid, BHT and BHA.

The preferred pharmaceutical compositions from the standpoint of ease ofpreparation and administration are solid compositions, particularlytablets and hardfilled or liquid-filled capsules. Oral administration ofthe compounds is preferred.

These active compounds may also be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacologically acceptable salt can be prepared inwater suitably mixed with a surfactant such as hydroxylpropylcellulose.Dispersions can also be prepared in glycerol, liquid, polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ofdispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syring ability exits. It must be stable underconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacterial and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), suitable mixtures thereof, and vegetable oil.

The following non-limiting examples illustrate preparation and use ofthe compounds of the invention.

EXAMPLE 1 A. 2-Amino-5-bromo-1-ethoxycarbonylmethyl-pyridinium; bromide

2-Amino-5-bromopyridine (10.88 g, 62.9 mmol) was dissolved in acetone(65 mL). To this solution was added ethyl bromoacetate (7.7 mL, 69.2mmol). The solution was heated to reflux overnight under nitrogen. Thereaction mixture was cooled and an off-white solid was filtered off. Thesolid was washed with acetone and dried to provide title compound as anoff-white solid (13.74 g, 64%). ¹H NMR (DMSO-d₆) δ 8.91 (s, 2H), 8.42(d, J=2.2 Hz, 1H), 8.09 (dd, J=2.2 and 9.5 Hz, 1H), 7.10 (d, J=9.5 Hz,1H), 5.11 (s, 2H), 4.21 (q, J=7.1 and 14.2, 2H), 1.26 (t, J=7.1, 3H); MS(m/e): 259 (MH⁺).

B. 6-Bromo-imidazo[1,2-a]pyridin-2-one

To a solution of 2-Amino-5-bromo-1-ethoxycarbonylmethyl-pyridinium;bromide (2.86 g, 8.4 mmol) in methanol (30 mL) was added sodiummethoxide (25 wt %, 2.5 mL, 10.1 mmol). The reaction mixture was stirredat room temperature overnight under argon. The reaction mixture wasdiluted with water and then extracted three times with ethyl acetate.The organic extracts were washed with brine, dried over magnesiumsulfate, filtered, evaporated to yield a tan solid. The crude materialwas purified by column chromatography eluting with 3, 5, and 10%methanol/dichloromethane. The product was obtained as a brown solid (56mg, 3%). ¹H NMR (CDCl₃) δ 7.85 (s, 1H), 7.67 (dd, J=1.6, 9.5 Hz, 1H),7.07 (d, J=9.5 Hz, 1H), 4.52 (s, 2H); MS (m/e): 215 (MH⁺); HRMS: calc'dMH⁺ for C₇H₅BrN₂O 212.9672; found 212.9664.

C1. 6-Bromo-3,3-dimethyl-imidazo[1,2-a]pyridin-2-one

A solution of 2-Amino-5-bromo-1-ethoxycarbonylmethyl-pyridinium; bromide(6.11 g, 17.97 mmol) in 100 mL of ethanol was prepared followed bysodium ethoxide (21 wt %, 20.5 mL, 54.9 mmol). After one hour,iodomethane was added (2.3 mL, 37.7 mmol) and the reaction was stirredat room temperature overnight. The solvent was evaporated and theresidue was taken up in dichloromethane. The mixture was filtered andthe filtrate was purified by column chromatography eluting with 5%methanol/dichloromethane. The product was obtained as a tan solid (1.07g, 25%). ¹H NMR (CDCl₃) δ 7.73 (s, 1H), 7.67 (dd, J=1.8 and 9.4 Hz, 1H),7.13 (d, J=9.4 Hz, 1H), 1.59 (s, 6H); MS (m/e): 241 (MH⁺).

C2. 6-Bromo-3,3-spiro[cyclopentane]-imidazo[1,2-a]pyridin-2-one

6-Bromo-imidazo[1,2-a]pyridin-2-one (0.211 g 1 mmol), NaOMe (25% inMeOH, 0.26 g, 1.2 mmole), was stirred in MeOH (5.0 mL). 1,4-Diiodobutane(0.310 g, 1.0 mmol) was added slowly. This was stirred at ambienttemperature for 16 hours. The reaction mixture was diluted with waterand then extracted three times with ethyl acetate. The organic extractswere washed with brine, dried over magnesium sulfate, filtered,evaporated to yield a tan solid. The crude material was purified bycolumn chromatography eluting with 5% methanol/dichloromethane. Theproduct was obtained as a white solid (20 mg, 20%). Several runs withdifferent scale was carried out and the best yield is 50%. ¹H NMR(CDCl₃) δ 7.68 (s, 1H), 7.62 (d, 1H, J=12 Hz), 7.04 (d, 1H, J=12 Hz),2.52-1.83 (m, 8H); MS (m/e): 267(MH⁺).

C3. 6-Bromo-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one

A solution of 2-Amino-5-bromo-1-ethoxycarbonylmethyl-pyridinium; bromide(4.66 g, 13.70 mmol) in 80 mL of ethanol was prepared followed by sodiumethoxide (21 wt %, 15.4 mL, 41.11 mmol). After one hour,1,5-diiodopentane was added (2.2 mL, 15.07 mmol) and the reactionallowed to proceed overnight. The reaction mixture was diluted withwater and then extracted three times with ethyl acetate. The organicextracts were washed with brine, dried over magnesium sulfate, filtered,evaporated to yield a tan solid. The crude material was purified bycolumn chromatography eluting with 5% methanol/dichloromethane. Theproduct was obtained as an orange solid (1.15 g, 30%). ¹H NMR (CDCl₃) δ7.73 (d, J=1.8 Hz, 1H), 7.63 (dd, J=2.2 and 9.4 Hz, 1H), 7.07 (d, J=9.0Hz, 1H), 2.35-2.24 (m, 2H), 2.01-1.96 (m, 2H), 1.88-1.81 (m, 1H),1.75-1.64 (m, 4H), 1.46-1.37 (s, 1H); MS (m/e): 282(MH⁺).

EXAMPLE 2 6-(3-Chloro-phenyl)-3,3-dimethyl-imidazo[1,2-a]pyridin-2-one

To a round-bottom flask was added6-bromo-3,3-dimethyl-imidazo[1,2-a]pyridin-2-one (60 mg, 0.25 mmol),3-chlorophenylboronic acid (39 mg, 0.25 mmol), potassium carbonate (69mg, 0.25 mmol), Pd(PPh₃)₄ (29 mg, 0.025 mmol), dioxane (5 mL) and water(1 mL). The mixture was heated at reflux until the starting material wasconsumed monitored by HPLC-MS. The solution was cooled and water wasadded. The reaction mixture was extracted twice with ethyl acetate andthe combined organic layers were dried, filtered and concentrated. Theresidue was purified by column chromatography eluting with 5%methanol/dichloromethane to provide the desired product as an off-whitesolid (43 mg, 63%). ¹H NMR (CDCl₃) δ 7.84 (dd, J=1.8 and 9.1 Hz, 1H),7.74 (s, 1H), 7.46-7.27 (m, 5H), 1.64 (s, 6H); MS (m/e): 273 (MH⁺);HRMS: calc'd MH⁺ for C₁₅H₁₃ClN₂O 273.0794; found 273.0800.

EXAMPLE 36-(3-chloro-phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one

The title compound was prepared in 71% yield according to the proceduredescribed in Example 2, starting from6-bromo-3,3-spiro[cyclohepane]-imidazo[1,2-a]pyridin-2-one and thecorresponding boronic acid. ¹H NMR (CDCl₃) δ 7.81 (dd, J=2.1 and 9.2 Hz,1H), 7.76 (d, J=1.4, 1H), 7.45-7.33 (m, 3H), 7.25-7.23 (m, 2H),2.40-2.30 (m, 2H), 2.05-2.00 (m, 2H), 1.91-1.86 (m, 1H), 1.78-1.71 (m,4H), 1.49-1.42 (m, 1H); MS (m/e): 313 (MH⁺).

EXAMPLE 43-(3,3-Dimethyl-2-oxo-2,3-dihydro-imidazo[1,2-a]pyridin-6-yl)-benzonitrile(JNJ-27385696)

The title product was prepared in 12% yield as a yellow solid accordingto the procedure described in Example 2 using 3-cyanophenylboronic acidas starting material. ¹H NMR (CDCl₃) δ 7.82 (dd, J=2.1 and 9.2 Hz, 1H),7.76-7.69 (m, 4H), 7.61 (m, 1H), 7.31 (d, J=9.3 Hz, 1H), 1.65 (s, 6H);MS (m/e): 264(MH⁺); HRMS: calc'd MH⁺ for C₁₆H₁₃N₃O 264.1137; found264.1130.

EXAMPLE 5 6-Chloro-3,3-dimethyl-imidazo[1,2-a]pyridin-2-one

The title compound was prepared in 44% yield according to the proceduredescribed in Example 1-C1, starting from 5-chloro-pyridin-2-ylamine. ¹HNMR (CDCl₃) δ 7.62 (d, J=2.2 Hz, 1H), 7.57 (dd, J=2.3 and 9.5 Hz, 1H),7.16 (d, J=9.5 Hz, 1H), 1.59 (s, 6H); MS (m/e): 197 (MH⁺).

EXAMPLE 6 6-Chloro-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one

The title compound was prepared in 14% yield according to the proceduredescribed in Example 1-C3, starting from 5-chloro-pyridin-2-ylamine. ¹HNMR (CDCl₃) δ 7.63 (t, J=1.8 and 0.4 Hz, 1H), 7.53 (dd, J=2.3 and 9.4Hz, 1H), 7.11 (dd, J=0.4, 9.4 Hz, 1H), 2.36-2.25 (m, 2H), 2.00-1.96 (m,2H), 1.88-1.81 (m, 1H), 1.75-1.63 (m, 4H), 1.46-1.36 (m, 1H); MS (m/e):237 (MH⁺).

EXAMPLE 76-(3,5-Difluoro-phenyl)-3,3-dimethyl-imidazo[1,2-a]pyridin-2-one(JNJ-27446913)

The title product was prepared in 73% yield as a yellow solid accordingto the procedure described in Example 2 using 3,5-difluorophenylboronicacid as starting material. ¹H NMR (CDCl₃) δ 7.81 (dd, J=2.1 and 9.2 Hz,1H), 7.77 (d, J=1.4 Hz, 1H), 7.29 (d, J=0.6 Hz, 1H), 7.02-6.98 (m, 2H),6.90-6.84 (m, 1H), 1.64 (s, 6H); MS (m/e): 275(MH⁺); HRMS: calc'd MH⁺for C₁₅H₁₂FN₂O 275.0996; found 275.1009.

EXAMPLE 8 3,3-Dimethyl-6-(3-nitro-phenyl)-imidazo[1,2-a]pyridin-2-one(JNJ-27504646)

The title product was prepared in 37% yield as a yellow solid accordingto the procedure described in Example 2, using 3-nitrophenylboronic acidas starting material. ¹H NMR (400 MHz, CDCl₃) δ 8.35 (t, J=2.0 Hz, 1H),8.30-8.27 (m, 1H), 7.89 (dd, J=2.1 and 9.2 Hz, 1H), 7.83-7.80 (m, 2H),7.70 (t, J=8.0 Hz, 1H), 7.33 (d, J=9.3 Hz, 1H), 1.66 (s, 6H); MS (m/e):284 (MH⁺); HRMS calc'd MH⁺ for C₁₅H₁₃N₃O₃ 284.1035; found 284.1028.

EXAMPLE 93,3-Dimethyl-6-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-2-one(JNJ-27512277)

The title product was prepared in 73% yield as an off-white solidaccording to the procedure described in Example 2, using3-trifluoromethylphenylboronic acid as starting material. ¹H NMR (CDCl₃)δ 7.86 (dd, J=2.1 and 9.2 Hz, 1H), 7.76 (s, J=1.5 Hz, 1H), 7.70-7.61 (m,4H), 7.30 (d, J=9.2, 1H), 1.65 (s, 6H); MS (m/e): 307 (MH⁺); HRMS:calc'd MH⁺ for C₁₆H₁₃F₃N₂O 307.1058; found 307.1052.

EXAMPLE 106-(2,4-Difluoro-phenyl)-3,3-dimethyl-imidazo[1,2-a]pyridin-2-one(JNJ-27518738)

The title product was prepared in 65% yield as a white solid accordingto the procedure described in Example 2 using 2,4-di-fluorophenylboronicacid as starting material. ¹H NMR (CDCl₃) δ 7.78-7.74 (m, 2H), 7.37 (m,1H), 7.28-7.26 (m, 1H), 7.05-6.95 (m, 2H), 1.62 (s, 6H); MS (m/e): 275(MH⁺); HRMS: calc'd MH⁺ for C₁₅H₁₂FN₂O 275.0996; found 275.1008.

EXAMPLE 116-(3,5-Bis-trifluoromethyl-phenyl)-3,3-dimethyl-imidazo[1,2-a]pyridin-2-one(27518803)

The title compound was prepared in 75% yield according to the proceduredescribed in Example 2, starting from 3,5-di-trifluoromethylphenylboronic acid. ¹H NMR (CDCl₃) δ 7.93-7.91 (m, 3H), 7.88-7.86 (m, 2H),7.33 (dd, J=1.8 and 8.4 Hz, 1H), 1.67 (s, 6H); MS (m/e): 375 (MH⁺).

EXAMPLE 12 6-(3-Methoxy-phenyl)-3,3-dimethyl-imidazo[1,2-a]pyridin-2-one

The title compound was prepared in 54% yield according to the proceduredescribed in Example 2, starting from6-bromo-3,3-dimethyl-imidazo[1,2-a]pyridin-2-one and 3-methoxyphenylboronic acid. ¹H NMR (CDCl₃) δ7.86 (dd, J=2.1 and 9.2 Hz, 1H), 7.73 (d,J=1.5 Hz, 1H), 7.43-7.39 (m, 1H), 7.28-7.25 (m, 1H), 7.05 (m, 1H),6.97-6.94 (m, 2H), 3.88 (s, 3H), 1.63 (s, 6H); MS (m/e): 269 (MH⁺).

EXAMPLE 13 6-(3-Fluoro-phenyl)-3,3-dimethyl-imidazo[1,2-a]pyridin-2-one

The title compound was prepared in 72% yield according to the proceduredescribed in Example 2, starting from6-bromo-3,3-dimethyl-imidazo[1,2-a]pyridin-2-one and the correspondingboronic acid. ¹H NMR (CDCl₃) δ 7.84 (dd, J=2.1 and 9.2 Hz, 1H), 7.75 (d,J=1.6 Hz, 1H), 7.49-7.43 (m, 1H), 7.29-7.24 (m, 2H), 7.19-7.10 (m, 2H),1.64 (m, 6H); MS (m/e): 257 (MH⁺).

EXAMPLE 14 6-(2-Chloro-phenyl)-3,3-dimethyl-imidazo[1,2-a]pyridin-2-one

The title compound was prepared in 46% yield according to the proceduredescribed in Example 2, starting from6-bromo-3,3-dimethyl-imidazo[1,2-a]pyridin-2-one and the correspondingboronic acid. ¹H NMR (CDCl₃) δ 7.77-7.73 (m, 2H), 7.55-7.51 (m, 1H),7.40-7.32 (m, 3H), 7.28-7.23 (m, 1H), 1.62 (s, 6H); MS (m/e): 273 (MH⁺).

EXAMPLE 156-(3-Fluro-phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one

The title compound was prepared in 39% yield according to the proceduredescribed in Example 2, starting from6-bromo-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one and thecorresponding boronic acid. ¹H NMR (CDCl₃) δ 7.81 (dd, J=2.1 and 9.2 Hz,1H), 7.77 (d, J=1.4, 1H), 7.50-7.40 (m, 1H), 7.25-7.23 (m, 2H),7.18-7.10 (m, 2H), 2.40-2.30 (m, 2H), 2.05-2.00 (m, 2H), 1.91-1.81 (m,1H), 1.77-1.71 (m, 4H), 1.50-1.38 (m, 1H); MS (m/e): 297 (MH⁺).

EXAMPLE 166-(3-Methoxy-phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one

The title compound was prepared in 67% yield according to the proceduredescribed in Example 2, starting from6-bromo-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one and thecorresponding boronic acid. ¹H NMR (CDCl₃) δ 7.83 (dd, J=2.1 and 9.2 Hz,1H), 7.77 (d, J=1.4 Hz, 1H), 7.40-7.38 (m, 1H), 7.24-7.22 (m, 1H),7.04-7.02 (m, 1H), 6.97-6.95 (m, 2H), 3.88 (s, 3H), 2.40-2.30 (m, 2H),2.05-2.00 (m, 2H), 1.92-1.80 (s, 1H), 1.77-1.68 (m, 4H), 1.50-1.38 (m,1H); MS (m/e): 309 (MH⁺).

EXAMPLE 176-(3,5-Bis-trifluoromethyl-phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one

The title compound was prepared in 35% yield according to the proceduredescribed in Example 2, starting from6-bromo-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one and thecorresponding boronic acid. ¹H NMR (CDCl₃) δ 7.93-7.79 (m, 5H),7.30-7.28 (m, 1H), 2.40-2.36 (m, 2H), 2.06-2.01 (m, 2H), 1.92-1.88 (m,1H), 1.82-1.72 (m, 4H), 1.50-1.38 (m, 1H); MS (m/e): 415 (MH⁺).

EXAMPLE 186-(3-nitro-phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one

The title compound was prepared in 8% yield according to the proceduredescribed in Example 2, starting from6-bromo-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one and thecorresponding boronic acid. ¹H NMR (CDCl₃) δ 8.34 (t, J=1.9 Hz, 1H),8.29-8.26 (m, 1H), 7.88-7.79 (m, 3H), 7.69 (t, J=7.9, 1H), 7.31-7.26 (m,1H), 2.45-2.30 (m, 2H), 2.10-2.00 (m, 2H), 1.93-1.83 (m, 1H), 1.81-1.70(m, 4H), 1.50-1.40 (m, 1H); MS (m/e): 324 (MH⁺).

EXAMPLE 196-(3-trifluoromethyl-phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one

The title compound was prepared in 65% yield according to the proceduredescribed in Example 2, starting from6-bromo-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one and thecorresponding boronic acid. ¹H NMR (CDCl₃) δ 7.84 (dd, J=2.2 and 9.2 Hz,1H), 7.78 (d, J=1.4 Hz, 1H), 7.69-7.62 (m, 4H), 7.28-7.25 (m, 1H),2.39-2.32 (m, 2H), 2.05-2.00 (m, 2H), 1.91-1.86 (m, 1H), 1.80-1.71 (m,4H), 1.47-1.43 (m, 1H); MS (m/e): 347 (MH⁺).

EXAMPLE 206-(3-cyano-phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one

The title compound was prepared in 47% yield according to the proceduredescribed in Example 2, starting from6-bromo-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one and thecorresponding boronic acid. ¹H NMR (CDCl₃) δ 7.82-7.79 (m, 2H),7.77-7.70 (m, 3H), 7.28-7.26 (m, 1H), 7.28-7.26 (m, 1H), 2.38-2.30 (m,2H), 2.05-2.01 (m, 2H), 1.91-1.87 (m, 1H), 1.80-1.71 (m, 4H), 1.49-1.43(m, 1H); MS (m/e): 304 (MH⁺).

EXAMPLE 216-(3,5-Difluoro-phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one

The title compound was prepared in 36% yield according to the proceduredescribed in Example 2, starting from6-bromo-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one and thecorresponding boronic acid. ¹H NMR (CDCl₃) δ 7.78-7.75 (m, 2H), 7.23 (s,1H), 7.00-6.97 (m, 2H), 6.90-6.84 (m, 1H), 2.40-2.23 (m, 2H), 2.05-1.95(m, 2H), 1.91-1.81 (m, 1H), 1.77-1.65 (m, 4H), 1.50-1.37 (m, 1H); MS(m/e): 315 (MH⁺).

EXAMPLE 226-(3,5-Dichloro-phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one

The title compound was prepared in 48% yield according to the proceduredescribed in Example 2, starting from6-bromo-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one and thecorresponding boronic acid. ¹H NMR (CDCl₃) δ 7.79-7.76 (m, 1H),7.69-7.64 (m, 1H), 7.58-7.53 (m, 1H), 7.49-7.45 (m, 1H), 7.31-7.23 (m,2H), 2.38-2.30 (m, 2H), 2.04-2.00 (m, 2H), 1.90-1.85 (m, 1H), 1.79-1.65(m, 4H), 1.50-1.38 (m, 1H); MS (m/e): 347 (MH⁺).

EXAMPLE 236-(2,4-Difluoro-phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one

The title compound was prepared in 48% yield according to the proceduredescribed in Example 2, starting from6-bromo-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one and thecorresponding boronic acid. ¹H NMR (CDCl₃) δ 7.81 (s, 1H), 7.75-7.72 (m,1H), 7.40-7.33 (m, 1H), 7.25-7.22 (m, 1H), 7.08-6.95 (m, 2H), 2.37-2.28(m, 2H), 2.05-2.02 (m, 2H), 1.87-1.84 (m, 1H), 1.75-1.71 (m, 4H),1.45-1.39 (m, 1H); MS (m/e): 315 (MH⁺).

EXAMPLE 246-(3-chloro-phenyl)-3,3-spiro[pentane]-imidazo[1,2-a]pyridin-2-one

The title compound was prepared in 60% yield according to the proceduredescribed in Example 2, starting from6-bromo-3,3-spiro[cyclopenane]-imidazo[1,2-a]pyridin-2-one and thecorresponding boronic acid. ¹H NMR (CDCl₃) δ 7.80 (dd, J=2.1 and 9.2 Hz,1H), 7.73 (d, J=1.6 Hz, 1H), 7.45-7.39 (m, 3H), 7.34-7.31 (m, 1H),7.25-7.23 (m, 1H), 2.53-2.48 (m, 2H), 2.20-2.16 (m, 2H), 2.05-1.94 (m,4H); MS (m/e): 299 (MH⁺).

EXAMPLE 256-(3-cyano-phenyl)-3,3-spiro[pentane]-imidazo[1,2-a]pyridin-2-one

The title compound was prepared in 31% yield according to the proceduredescribed in Example 2, starting from6-bromo-3,3-spiro[cyclopenane]-imidazo[1,2-a]pyridin-2-one and thecorresponding boronic acid. ¹H NMR (CDCl₃) δ 7.80 (dd, J=2.2 and 9.2 Hz,1H), 7.75-7.68 (m, 4H), 7.62 (t, J=7.7 Hz, 1H), 7.28 (s, 1H), 2.55-2.48(m, 2H), 2.22-2.18 (m, 2H), 2.06-1.95 (m, 4H); MS (m/e): 290 (MH⁺).

EXAMPLE 266-(3-Fluoro-phenyl)-3,3-spiro[pentane]-imidazo[1,2-a]pyridin-2-one

The title compound was prepared in 58% yield according to the proceduredescribed in Example 2, starting from6-bromo-3,3-spiro[cyclopenane]-imidazo[1,2-a]pyridin-2-one and thecorresponding boronic acid. ¹H NMR (CDCl₃) δ 7.81 (dd, J=2.0 and 9.1 Hz,1H), 7.74 (d, J=1.8 Hz, 1H), 7.49-7.43 (m, 1H), 7.27-7.22 (m, 2H),7.17-7.10 (m, 2H), 2.54-2.48 (m, 2H), 2.21-2.14 (m, 2H), 2.08-1.94 (m,4H); MS (m/e): 283 (MH⁺).

EXAMPLE 276-(3-nitro-phenyl)-3,3-spiro[pentane]-imidazo[1,2-a]pyridin-2-one

The title compound was prepared in 48% yield according to the proceduredescribed in Example 2, starting from6-bromo-3,3-spiro[cyclopenane]-imidazo[1,2-a]pyridin-2-one and thecorresponding boronic acid. ¹H NMR (CDCl₃) δ 8.33 (t, J=2.0 Hz, 1H),8.29-8.27 (m, 1H), 7.87 (dd, J=2.1 and 9.2 Hz, 1H), 7.83-7.68 (m, 2H),7.70 (t, J=8.0 Hz, 1H), 7.30 (d, J=9.2 Hz, 1H), 2.54-2.49 (m, 2H),2.22-2.18 (m, 2H), 2.07-1.97 (m, 4H); MS (m/e): 310 (MH⁺).

EXAMPLE 286-(3,4-Dichloro-phenyl)-3,3-spiro[pentane]-imidazo[1,2-a]pyridin-2-one

The title compound was prepared in 58% yield according to the proceduredescribed in Example 2, starting from6-bromo-3,3-spiro[cyclopenane]-imidazo[1,2-a]pyridin-2-one and thecorresponding boronic acid. ¹H NMR (CDCl₃) δ 7.77 (dd, J=2.1 and 9.2 Hz,1H), 7.72 (m, 1H), 7.57-7.53 (m, 2H), 7.30-7.23 (m, 2H), 2.53-2.47 (m,2H), 2.21-2.14 (m, 2H), 2.08-1.94 (m, 4H); MS (m/e): 331 (MH⁻).

EXAMPLE 296-(3,5-Bis-trifluoromethyl-phenyl)-3,3-spiro[pentane]-imidazo[1,2-a]pyridin-2-one

The title compound was prepared in 80% yield according to the proceduredescribed in Example 2, starting from6-bromo-3,3-spiro[cyclopenane]-imidazo[1,2-a]pyridin-2-one and thecorresponding boronic acid. ¹H NMR (CDCl₃) δ 7.93 (s, 1H), 7.88 (s, 2H),7.84-7.79 (m, 2H), 7.30-7.28 (m, 1H), 2.54-2.48 (m, 2H), 2.23-2.16 (m,2H), 2.09-1.97 (m, 4H); MS (m/e): 401 (MH⁺).

EXAMPLE 306-(3-Chloro-4-fluoro-phenyl)-3,3-spiro[pentane]-imidazo[1,2-a]pyridin-2-one

The title compound was prepared in 44% yield according to the proceduredescribed in Example 2, starting from6-bromo-3,3-spiro[cyclopenane]-imidazo[1,2-a]pyridin-2-one and thecorresponding boronic acid. ¹H NMR (CDCl₃) δ 7.76 (dd, J=2.1 and 9.2 Hz,1H), 7.70 (d, J=1.4 Hz, 1H), 7.49 (dd, J=2.3 and 6.7 Hz, 1H), 7.34-7.22(m, 3H), 2.53-2.47 (m, 2H), 2.22-2.12 (m, 2H), 2.07-1.94 (m, 4H); MS(m/e): 317 (MH⁺).

EXAMPLE 31 A.5-(3-Fluoro-phenyl)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one

The title compound was prepared in 32% yield according to the proceduredescribed in Example 2, starting from5-bromo-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (prepared according tothe procedure described in WO2003082868, Page 33) and 3-fluoro-phenylboronic acid. ¹H NMR is the same as the one reported in WO2003082868,page 34.

B.5-(3-Fluoro-phenyl)-3,3-dimethyl-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one

A solution of5-(3-Fluoro-phenyl)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (91 mg, 0.40mmol) in THF (8 mL) was cooled to between −10 and −30° C. under argon.To this solution was added n-butyllithium (0.34 mL, 0.84 mmol) followedby N,N,N′,N′-tetramethylenediamine (0.13 mL, 0.84 mmol). The solutionwas stirred at −10° C. for 0.5 hours. Iodomethane was added (0.05 mL,0.84 mmol) and the solution was allowed to warm to room temperatureovernight. The reaction mixture was diluted with water and thenextracted three times with ethyl acetate. The organic extracts werewashed with brine, dried over magnesium sulfate, filtered, evaporated toyield a tan solid. The crude material was purified by columnchromatography eluting with 40% ethyl acetate/hexanes. The product wasobtained as off-white solid (23 mg, 22%). ¹H NMR (CDCl₃) δ 8.74 (s, 1H),8.36 (d, J=1.9 Hz, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.46-7.41 (m, 1H), 7.33(d, J=7.8 Hz, 1H), 7.24-7.23 (m, 1H), 7.11-7.06 (m, 1H), 1.48 (s, 6H);MS (m/e): 257 (MH⁺).

EXAMPLE 325-(3-Fluoro-phenyl)-3,3-spiro[cyclohxane]-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one

The title compound was prepared in 24% yield according to the proceduredescribed in Example 30B, starting from5-(3-Fluoro-phenyl)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one and1,5-diiodopentane. ¹H NMR (CDCl₃) δ 9.40 (s, 1H), 8.37 (s, 1H), 7.87 (d,J=1.9 Hz, 1H), 7.47-7.38 (m, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.24-7.23 (m,1H), 7.11-7.06 (m, 1H), 1.99-1.67 (m, 10H); MS (m/e): 297 (MH⁺).

EXAMPLE 33 In Vitro Test

T47D human breast cancer cells are grown in RPMI medium without phenolred (Invitrogen) containing 10% (v/v) heat-inactivated fetal bovineserum (FBS; Hyclone), 1% (v/v) penicillin-streptomycin (Invitrogen), 1%(w/v) glutamine (Invitrogen), and 10 mg/mL insulin (Sigma). Incubationconditions are 37 □C in a humidified 5% (v/v) carbon dioxideenvironment. For assay, the cells are plated in 96-well tissue cultureplates at 10,000 cells per well in assay medium [RPMI medium withoutphenol red (Invitrogen) containing 5% (v/v) charcoal-treated FBS(Hyclone) and 1% (v/v) penicillin-streptomycin (Invitrogen)]. Two dayslater, the medium is decanted and the compounds are added in a finalconcentration of 0.1% (v/v) dimethyl sulfoxide in fresh assay medium.Twenty-four hours later, an alkaline phosphatase assay is performedusing a SEAP kit (BD Biosciences Clontech, Palo Alto, Calif.). Briefly,the medium is decanted and the cells are fixed for 30 minutes at roomtemperature with 5% (v/v) formalin (Sigma). The cells are washed oncewith room temperature Hank's buffered saline solution (Invitrogen).Equal volumes (0.05 mL) of 1× Dilution Buffer, Assay Buffer and 1:20substrate/enhancer mixture are added. After 1-hour incubation at roomtemperature in the dark, the lysate is transferred to a white 96 wellplate (Dynex) and luminescence is read using a LuminoSkan Ascent (ThermoElectron, Woburn, Mass.).

TABLE 3

Ex. # R₁, R₂ R₄ % inh. 1-C3 Spirocyclohexane Br 3 Spirocyclohexyl3-Cl-phenyl  104% 1-C1 Dimethyl Br   53% 2 Dimethyl 3-Cl-phenyl   15% 4Dimethyl 3-CN-phenyl   19% 5 Dimethyl Cl   31% 6 Spirocyclohexyl Cl  42% 7 Dimethyl 3,5-di-F-phenyl   40% 8 Dimethyl 3-NO₂-phenyl   33% 9Dimethyl 3-CF₃-phenyl   17% 10 Dimethyl 2,4-di-F-phenyl   29% 11Dimethyl 3,5-di-CF₃-phenyl   19% 12 Dimethyl 3-MeO-phenyl  3.1% 13Dimethyl 3-F-phenyl   14% 14 Dimethyl 2-Cl-phenyl   0% 1-C2spirocyclopentane Br   35% 15 spirocyclohexane 3-F-phenyl   0% 16spirocyclohexane 3-MeO-phenyl   01% 17 spirocyclohexane3,5-di-CF₃-phenyl   04% 18 spirocyclohexane 3-NO₂-phenyl   98% 19spirocyclohexane 3-CF₃-phenyl   97% 20 spirocyclohexane 3-CN-phenyl  96% 21 spirocyclohexane 3,5-di-F-phenyl   99% 22 spirocyclohexane3,4-di-Cl-phenyl   88% 23 spirocyclohexane 2,4-di-F-phenyl   96% 24spirocyclopentane 3-Cl-phenyl   1% 25 spirocyclopentane 3-CN-phenyl   2%26 spirocyclopentane 3-F-phenyl   2% 27 spirocyclopentane 3-NO₂-phenyl  86% *28 spirocyclopentane 3,4-di-Cl-phenyl   22% 29 spirocyclopentane3,5-di-CF₃-phenyl   25% 30 spirocyclopentane 3-Cl-4-F-phenyl   21% *%activation: 93.82% @ 3000 nM, EC50 = 1950 nM.

TABLE 4

Ex. # R₁, R₂ R₃ % inh. IC₅₀ (nM) 31 Spirocyclo 3-F-phenyl 92% @ 10 uM4484 hexane 95% @ 3 uM 32 Dimethyl 3-F-phenyl 58% @ 10 uM 7027 58% @ 3uM

EXAMPLE 34

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A compound of formula (1):

wherein: R₁, R₂ are connected by —(CH₂)₄— to form a 5-membered spiroring or R₁, R₂ are connected by —(CH₂)₅— to form a 6-membered spiroring: R₃ is halogen, nitro, cyano and methoxy substituted phenyl, or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1selected from the group consisting of:6-(3-nitro-phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one,6-(3-trifluoromethyl-phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one,6-(3-cyano-phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one,6-(3,5-Difluoro-phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one,6-(3,5-Dichloro-phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one,and6-(2,4-Difluoro-phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one.